Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells

Abstract

Here, we show that new mitochondrial biogenesis is required for the anchorage independent survival and propagation of cancer stem-like cells (CSCs). More specifically, we used the drug XCT790 as an investigational tool, as it functions as a specific inhibitor of the ERRα-PGC1 signaling pathway, which governs mitochondrial biogenesis. Interestingly, our results directly demonstrate that XCT790 efficiently blocks both the survival and propagation of tumor initiating stem-like cells (TICs), using the MCF7 cell line as a model system. Mechanistically, we show that XCT790 suppresses the activity of several independent signaling pathways that are normally required for the survival of CSCs, such as Sonic hedgehog, TGFβ-SMAD, STAT3, and Wnt signaling. We also show that XCT790 markedly reduces oxidative mitochondrial metabolism (OXPHOS) and that XCT790-mediated inhibition of CSC propagation can be prevented or reversed by Acetyl-L-Carnitine (ALCAR), a mitochondrial fuel. Consistent with our findings, over-expression of ERRα significantly enhances the efficiency of mammosphere formation, which can be blocked by treatment with mitochondrial inhibitors. Similarly, mammosphere formation augmented by FOXM1, a downstream target of Wnt/β-catenin signaling, can also be blocked by treatment with three different classes of mitochondrial inhibitors (XCT790, oligomycin A, or doxycycline). In this context, our unbiased proteomics analysis reveals that FOXM1 drives the expression of >90 protein targets associated with mitochondrial biogenesis, glycolysis, the EMT and protein synthesis in MCF7 cells, processes which are characteristic of an anabolic CSC phenotype. Finally, doxycycline is an FDA-approved antibiotic, which is very well-tolerated in patients. As such, doxycycline could be re-purposed clinically as a ‘safe’ mitochondrial inhibitor, to target FOXM1 and mitochondrial biogenesis in CSCs, to prevent tumor recurrence and distant metastasis, thereby avoiding patient relapse.

The Role of PGC1α in Cancer Metabolism and its Therapeutic Implications

“…Furthermore, this pathway is also involved in hematopoietic stem cell maintenance (87,88). Although only a small number of studies reported the involvement of PGC1a in cancer stem cells, the metabolic profile of hematopoietic stem cells and cancer stem cells could have some common traits in stemness maintenance (79,(89)(90)(91). These studies provided evidence indicating that PML/ PGC1a/PPARa signaling is essential for maintaining cellular metabolic homeostasis with potential therapeutic implications.…”

The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology

“…65 Anchorageindependent growth can be enabled by MITF target genes such as PGC1α and c-Met. 45,[73][74][75][76] During anchorageindependent growth, mitochondrial reactive oxygen species induced by detachment of cancer cells from extracellular matrix 77 can be reduced by proteins upregulated by PGC1α. 45,75,76 c-Met has a key role in KRAS-dependent anchorage-independent growth in KRAS mutant cancers.…”

“…45,[73][74][75][76] During anchorageindependent growth, mitochondrial reactive oxygen species induced by detachment of cancer cells from extracellular matrix 77 can be reduced by proteins upregulated by PGC1α. 45,75,76 c-Met has a key role in KRAS-dependent anchorage-independent growth in KRAS mutant cancers. 74 The germline MITF E318K mutation was subsequently discovered by multiple groups to encode a familial melanoma gene and to increase the risk of both melanoma and renal cell carcinoma.…”

A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX

“…One aspect that all these antibiotics have in common is that they exert manageable anti-mitochondrial side-effects, which can be repurposed as their therapeutic effects, to eradicate CSCs [19,20]. More specifically, Doxcycyline and Azithromycin inhibit mitochondrial protein translation, effectively blocking new mitochondrial biogenesis [16–20].…”